Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the invention relates to novel substituted oxazolidinones, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of thromboembolic disorders.
• Blood coagulation is a protective mechanism of the organism which helps to “seal” defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum.
• Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered.
• Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of the cascade comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot.
• blood coagulation traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished.
• factor Xa which is formed from the proenzyme factor X, has a key role, since it joins both coagulation paths.
• the activated serine protease Xa cleaves prothrombin to thrombin.
• the thrombin formed cleaves fibrinogen to fibrin.
• Subsequent crosslinking of the fibrin monomers results in the formation of blood clots and thus haemostasis.
• thrombin is a potent trigger of platelet aggregation, which also contributes considerably to haemostasis.
• Haemostasis is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulation system or defective inhibition of the activation processes may lead to the formation of local thromboses or embolisms in vessels (arteries, veins, lymph vessels) or cardiac cavities. This may lead to serious thromboembolic disorders. In addition, hypercoagulability may—systemically—in the case of consumption coagulopathy lead to disseminated intravasal coagulation. Thromboembolic complications are furthermore encountered in microangiopathic haemolytic anaemias, extracorporeal circulatory systems, such as haemodialysis, and also prosthetic heart valves.
• Thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th edition, 1997, W.B. Saunders Company, Philadelphia].
• anticoagulants known from the prior art i.e. substances for inhibiting or preventing blood coagulation
• substances for inhibiting or preventing blood coagulation have various, frequently grave disadvantages. Accordingly, in practice, efficient treatment methods or the prophylaxis of thromboembolic disorders is found to be very difficult and unsatisfactory.
• heparin which is administered parenterally or subcutaneously.
• these days preference is increasingly given to low-molecular-weight heparin; however, this does likewise not avoid the known disadvantages, described hereinbelow, of heparin therapy.
• heparin is orally ineffective and has only a comparatively short half-life. Since heparin inhibits several factors of the blood coagulation cascade simultaneously, the action is unselective.
• a second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indanediones, but especially compounds such as warfarin, phenprocoumone, dicoumarole and other coumarin derivatives which unselectively inhibit the synthesis of various products of certain vitamin-K-dependent coagulation factors in the liver.
• the onset of activity is very slow (latency time to onset of action 36 to 48 hours).
• the compounds can be administered orally; however, owing to the high risk of bleeding and the narrow therapeutic index, complicated individual adjustment and observation of the patient is required [J. Hirsh, J. Dalen, D. R.
• factor Xa is one of the most important targets for anticoagulatory active compounds [J. Hauptmann, J. S. S. S. S. S. S. S. S. S. S. S. Raghavan, M. Dikshit, “Recent advances in the status and targets of antithrombotic agents” Drugs Fut. 2002, 27, 669-683; H. A. Wieland, V. Laux, D. Kozian, M.
• Oxazolidinones as non-peptidic, low-molecular-weight factor Xa inhibitors are described in WO 01/47919.
• the therapeutic width is of central importance: the difference between the therapeutically active dose for coagulation inhibition and the dose where bleeding may occur should be as big as possible so that maximum therapeutic activity is achieved at a minimum risk profile.
• the therapeutic width of an antithrombotically active compound depends on the changes in the plasma levels of an active compound during the course of the day after the administration of the medicament.
• the peak-to-trough ratio i.e. the ratio between the maximum level after administration of the medicament and the minimum level at the end of the treatment interval may be used as a measure for this.
• this peak-to-trough ratio should be as small as possible, so that the occurrence of bleeding by reduced maximum levels can be avoided and that sufficiently high minimum levels ensure antithrombotic activity during the entire treatment interval.
• the invention provides compounds of the formula
• R 1 represents a group of the formula
• R 4 represents hydrogen or C 1 -C 3 -alkyl, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy
• R 5 represents hydrogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy
• R 6 represents hydrogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, where alkyl and alkoxy
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds, comprised by formula (I), of the formulae mentioned below and their salts, solvates and solvates of the salts and the compounds, comprised by the formula (I), mentioned below as exemplary embodiments and their salts, solvates and solvates of the salts if the compounds, comprised by formula (I), mentioned below are not already salts, solvates and solvates of the salts.
• the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). Accordingly, the invention comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers, it is possible to isolate the stereoisomerically uniform components in a known manner.
• the present invention comprises all tautomeric forms.
• preferred salts are physiologically acceptable salts of the compounds according to the invention.
• the invention also comprises salts which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.
• Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tarta
• Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salt
• solvates are those forms of the compounds according to the invention which, in solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates where the coordination is with water. In the context of the present invention, preferred solvates are hydrates.
• the present invention also comprises prodrugs of the compounds according to the invention.
• prodrugs includes compounds which for their part may be biologically active or inactive but which, during the time they spend in the body, are converted into compounds according to the invention (for example metabolically or hydrolytically).
• alkyl per se and “alk” and “alkyl” in alkoxy represent a straight-chain alkyl radical having generally 1 to 3, preferably 1 or 2, carbon atoms, by way of example and by way of preference methyl, ethyl and n-propyl.
• alkoxy represents, by way of example and by way of preference, methoxy, ethoxy and n-propoxy.
• cycloalkyl represents a cycloalkyl group having generally 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms, by way of example and by way of preference cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• cycloalkyloxy represents a cycloalkyloxy group having generally 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms, by way of example and by way of preference cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
• the end point of the line which is marked by a # is not a carbon atom or a CH 2 group, but is part of the bond to the atom to which R 1 is attached.
• a symbol * at a carbon atom means that the compound is present in enantiomerically pure form with respect to the configuration at this carbon atom, which is, in the context of the present invention, to be understood as meaning an enantiomeric excess of more than 90% (>90% ee).
• R 1 represents a group of the formula
• R 4 represents hydrogen
• R 5 represents hydrogen, hydroxyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy
• R 6 represents hydrogen, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, where alkyl and alkoxy may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy
• R 8 represents hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl, where C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and C 1 -C 3 -alkoxy
• R 1 represents a group of the formula
• R 4 represents hydrogen
• R 5 represents hydrogen, hydroxyl or hydroxymethyl
• R 6 represents hydrogen, methyl, hydroxymethyl, 2-hydroxyeth-1-yl or 2-hydroxyeth-1-oxy
• R 8 represents hydrogen or methyl
• R 9 represents hydrogen or methyl
• R 10 represents methyl, ethyl or 2-hydroxyeth-1-yl
• R 2 represents fluorine or chlorine
• R 3 represents hydrogen or methyl, and their salts, their solvates and the solvates of their salts.
• R 1 represents a group of the formula
• # is the point of attachment to the phenyl ring
• R 4 is hydrogen
• R 5 is hydrogen, hydroxyl or hydroxymethyl
• R 6 is hydroxymethyl or 2-hydroxyeth-1-oxy
• R 2 is fluorine or chlorine
• R 3 is hydrogen or methyl
• R 4 represents hydrogen
• R 5 represents hydrogen, hydroxyl or hydroxymethyl
• R 6 represents hydroxymethyl, 2-hydroxyeth-1-yl or 2-hydroxyeth-1-oxy.
• R 4 represents hydrogen
• R 5 represents hydrogen, hydroxyl or hydroxymethyl.
• R 8 represents hydrogen or methyl
• R 9 represents hydrogen or methyl
• R 10 represents methyl, ethyl or 2-hydroxyeth-1-yl.
• radical definitions given in the respective combinations or preferred combinations of radicals are, independently of the respective given combinations of radicals, also replaced by radical definitions of other combinations.
• the invention furthermore provides a process for preparing the compounds of the formula (I), or salts, solvates or solvates of the salts thereof, wherein [A] the compound of the formula
• X represents halogen, preferably bromine or chlorine, or hydroxyl.
• hydroxyl groups are protected during the process, for example by a silyl protective group, these are removed after the process [A] or [B] has ended using methods known to the person skilled in the art, for example by reaction with tetrabutylammonium fluoride in a solvent, such as, for example, tetrahydrofuran.
• the free base of the salts can be obtained, for example, by chromatography on a reversed phase column using an acetonitrile/water gradient with addition of a base, in particular by using an RP18 Phenomenex Luna C18(2) column and diethylamine as base, or by dissolving the salts in an organic solvent and extracting with aqueous solutions of basic salts such as sodium bicarbonate.
• the invention furthermore provides a process for preparing the compounds of the formula (I) or solvates thereof wherein salts of the compounds or solvates of the salts of the compounds are converted by chromatography with addition of a base into the compounds.
• the reaction of the first step of process [A] is generally carried out in inert solvents, in the presence of a Lewis acid, preferably in a temperature range of from room temperature to reflux of the solvent at atmospheric pressure.
• Inert solvents are, for example, polar aprotic solvents, such as, for example, acetonitrile, butyronitrile, dichloromethane or chloroform; preference is given to acetonitrile.
• polar aprotic solvents such as, for example, acetonitrile, butyronitrile, dichloromethane or chloroform; preference is given to acetonitrile.
• Lewis acids are, for example, magnesium perchlorate, ytterbium(III) trifluoromethanesulphonate, or aluminium trichloride; preference is given to magnesium perchlorate.
• the reaction of the second step of process [A] is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of from room temperature to reflux of the solvent at atmospheric pressure.
• Inert solvents are, for example, polar aprotic solvents, such as, for example, acetonitrile or butyronitrile.
• Bases are, for example, strong tertiary amine bases, such as, for example, 4-N,N-dimethylaminopyridine.
• reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range of from ⁇ 30° C. to 50° C. at atmospheric pressure.
• Inert solvents are, for example, tetrahydrofuran, methylene chloride, pyridine, dioxane or dimethylformamide, preference is given to tetrahydrofuran or methylene chloride.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine;
• reaction is generally carried out in inert solvents, in the presence of a dehydrating agent, if appropriate in the presence of a base, preferably in a temperature range of from ⁇ 30° C. to 50° C. at atmospheric pressure.
• Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Particular preference is given to dichloromethane or dimethylformamide.
• suitable dehydrating agents are, for example, carbodiimides, such as, for example, N,N′-diethyl-, N,N,′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds, such as carbonyldiimideazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds, such as 2-ethoxy-1-ethoxycarbonyl-1,2-
• Bases are, for example, alkali metal carbonates, such as, for example, sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• alkali metal carbonates such as, for example, sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate
• organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• the condensation with HATU or with EDC is preferably carried out in the presence of HOBt.
• R 4 , R 5 , R 6 , R 10 and R 11 have the meaning given above.
• the reaction is generally carried out in inert solvents, in the presence of a copper(I) salt, a base and a diamine ligand, preferably in a temperature range of from 60° C. to reflux of the solvent at atmospheric pressure.
• Inert solvents are, for example, aprotic solvents, such as toluene, dioxane, tetrahydrofuran or dimethylformamide; preference is given to dioxane.
• aprotic solvents such as toluene, dioxane, tetrahydrofuran or dimethylformamide; preference is given to dioxane.
• Copper(I) salts are, for example, copper(I) iodide, copper(I) chloride or copper(I) oxide; preference is given to copper(I) iodide.
• Bases are, for example, potassium phosphate, potassium carbonate or caesium carbonate; preference is given to potassium phosphate.
• Diamine ligands are, for example, 1,2-diamines, such as N,N′-dimethylethylenediamine or 1,2-diaminocyclohexane; preference is given to N,N′-dimethylethylenediamine.
• reaction is followed by hydrogenolytic cleavage of the benzyl groups using reaction conditions known to the person skilled in the art, to give the compounds of the formula (III).
• reaction examples are given in the examples.
• the compounds of the formula (IX) are known or can be synthesized by known processes from the corresponding starting materials.
• R 7 , R 8 and R 12 have the meaning given above with a strong base and a zinc salt and, in the second step, without prior isolation, reacting the intermediate with compounds of the formula (IX) and a palladium complex, and, in the third step, removing the benzyl groups hydrogenolytically using reaction conditions known to the person skilled in the art.
• the reaction of the first step is generally carried out in inert solvents, preferably in a temperature range of from ⁇ 30° C. to 0° C. at atmospheric pressure.
• the reaction of the second step is generally carried out in inert solvents, preferably in a temperature range of from room temperature to reflux of the solvent at atmospheric pressure.
• Inert solvents for both reaction steps are, for example, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, if appropriate in a mixture with hydrocarbons, such as, for example, hexane; preference is given to tetrahydrofuran.
• Strong bases are, for example, sec-butyllithium, tert-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide; preference is given to sec-butyllithium.
• the zinc salt is, for example, zinc chloride.
• Palladium complexes are formed in situ from palladium compounds and ligands.
• Suitable palladium compounds are, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(di-benzylideneacetone)palladium(0); preference is given to bis(dibenzylideneacetone)palladium(0).
• Ligands are, for example, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, binaphthyl or N-heterocyclic carbene ligands; preference is given to 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.
• the reaction of the first step is generally carried out in inert solvents, if appropriate in the presence of a little water, in the presence of a base and a palladium catalyst, and also, if appropriate, in the presence of a ligand, preferably in a temperature range of from 40° C. to reflux of the solvent at atmospheric pressure.
• Inert solvents are, for example, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane; preference is given to 1,2-dimethoxyethane.
• Bases are, for example, sodium carbonate, potassium carbonate or caesium carbonate; preference is given to a 2 molar solution of sodium carbonate in water.
• Palladium compounds are, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0); preference is given to tetrakis(triphenylphosphine)palladium(0).
• Ligands are, for example, phosphine ligands which are stable to hydrolysis, such as triphenylphosphine.
• the reaction of the second step is generally carried out in inert solvents, in the presence of an acid, preferably in a temperature range of from 0° C. to room temperature at atmospheric pressure.
• Inert solvent/acid mixtures are, for example, hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane. Preference is given to hydrochloric acid in dioxane at room temperature.
• the compounds of the formula (III) can be prepared by reducing the nitro group in compounds of the formula
• the reaction is generally carried out using a reducing agent in inert solvents, preferably in a temperature range of from room temperature to reflux of the solvents at from atmospheric pressure to 3 bar.
• Reducing agents are, for example, palladium on activated carbon and hydrogen, tin dichloride or titanium trichloride; preference is given to palladium on activated carbon and hydrogen or tin dichloride.
• Inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine; preferred solvents are methanol, ethanol, isopropanol or, in the case of tin dichloride, dimethylformamide.
• ethers such as diethyl ether, methyl tert-butyl ether, 1,2-d
• the compounds of the formula (XI) are known or can be synthesized by known processes from the corresponding starting materials.
• the compounds of the formula (V) are known or can be prepared by removing the phthalimide protective group in compounds of the formula
• the reaction is generally carried out using an aqueous methylamine solution or a hydrazine hydrate solution in ethanol, preferably using an aqueous methylamine solution at reflux of the solvents under atmospheric pressure.
• the compounds of the formula (XII) are known, can be prepared from the corresponding epoxides as described under process [A] or can be synthesized by known processes from the corresponding starting materials.
• the compounds according to the invention have an unforeseeable useful spectrum of pharmacological activity.
• the compounds according to the invention are inhibitors of blood coagulation factor Xa acting, in particular, as anticoagulants.
• the compounds according to the invention have favourable physicochemical properties and a large therapeutic width, which is advantageous for their therapeutic application.
• the present invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, preferably thromboembolic disorders and/or thromboembolic complications.
• Thromboembolic disorders in the sense of the present invention are in particular disorders such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusion diseases, pulmonary embolisms, deep venous thromboses and kidney venous thromboses, transitory ischaemic attacks and also thrombotic and thromboembolic stroke.
• STEMI myocardial infarction with ST segment elevation
• non-STEMI non-STEMI
• stable angina pectoris unstable angina pectoris
• reocclusions reocclusions and restenoses after coronary interventions
• peripheral arterial occlusion diseases pulmonary embolisms
• deep venous thromboses and kidney venous thromboses transitory ischaemic attacks and also
• the substances according to the invention are also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, cerebral ischaemias, stroke and systemic thromboembolisms and ischaemias, in patients having acute, intermittent or persistent cardial arrhythmias, such as, for example, atrial fibrillation, and those undergoing cardioversion, furthermore in patients having cardiac valve disorders or having artifical cardiac valves.
• cardiogenic thromboembolisms such as, for example, cerebral ischaemias, stroke and systemic thromboembolisms and ischaemias
• Thromboembolic complications are furthermore encountered in microangiopathic haemolytic anaemias, extracorporeal circulatory systems, such as haemodialysis and prosthetic heart valves.
• the compounds according to the invention are also suitable for the prophylaxis and/or treatment of atherosclerotic vascular disorders and inflammatory disorders such as rheumatic disorders of the locomotor apparatus, and in addition also for the prophylaxis and/or treatment of Alzheimer's disease.
• the compounds according to the invention can be used for inhibiting tumour growth and formation of metastases, for microangiopathies, age-related macula degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular disorders, and also for the prevention and treatment of thromboembolic complications, such as, for example, venous thromboembolisms, for tumour patients, in particular those undergoing major surgical interventions or chemo- or radiotherapy.
• the compounds according to the invention are also suitable for the prophylaxis and/or treatment of pulmonary hypertension.
• pulmonary hypertension includes certain forms of pulmonary hypertension. Examples which may be mentioned are pulmonary arterial hypertension, pulmonary hypertension associated with disorders of the left heart, pulmonary hypertension associated with pulmonary disorders and/or hypoxia and pulmonary hypertension owing to chronic thromboembolisms (CTEPH).
• CTEPH chronic thromboembolisms
• pulmonary arterial hypertension includes certain forms of pulmonary hypertension, as determined, for example, by the World Health Organization (WHO) ( Clinical Classification of Pulmonary Hypertension , Venice 2003).
• WHO World Health Organization
• Pulmonary arterial hypersion comprises idiopathic pulmonary arterial hypertension (IPAH, formally also referred to as primary pulmonary hypertension), familiar pulmonary arterial hypertension (FPAH) and associated pulmonary-arterial hypertension (APAH), which is associated with collagenoses, congenital systemic-pulmonary shunt vitia, portal hypertension, HIV infections, the ingestion of certain drugs and medicaments, with other disorders (thyroid disorders, glycogen storage disorders, Morbus Gaucher, hereditary teleangiectasy, haemoglobinopathies, myeloproliferative disorders, splenectomy), with disorders having a significant venous/capillary contribution, such as pulmonary-venoocclusive disorder and pulmonary-capillary haemangiomatosis, and also persisting pulmonary hypertension of neonatants.
• IPH idiopathic pulmonary arterial hypertension
• FPAH familiar pulmonary arterial hypertension
• APAH pulmonary-arterial hypertension
• Pulmonary hypertension associated with disorders of the left heart comprises a diseased left atrium or ventricle and mitral or aorta valve defects.
• Pulmonary hypertension associated with pulmonary disorders and/or hypoxia comprises chronic obstructive pulmonary disorders, interstitial pulmonary disorder, sleep apnoea syndrome, alveolar hypoventilation, chronic high-altitude sickness and inherent defects.
• Pulmonary hypertension owing to chronic thromboembolisms comprises the thromboembolic occlusion of proximal pulmonary arteries, the thromboembolic occlusion of distal pulmonary arteries and non-thrombotic pulmonary embolisms (tumour, parasites, foreign bodies).
• the present invention furthermore provides the use of factor Xa inhibitors for preparing medicaments for the treatment and/or prophylaxis of pulmonary hypertension associated with sarcoidosis, histiocytosis X and lymphangiomatosis.
• the substances according to the invention may also be suitable for treating pulmonary and hepatic fibroses
• the compounds according to the invention may also be suitable for the treatment and/or prophylaxis of sepsis (or septicaemia), systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multiorgan failure, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), septic shock, DIC (disseminated intravascular coagulation or consumption coagulopathy) and/or septic organ failure.
• SIRS systemic inflammatory syndrome
• septic organ dysfunction e.g., septic organ dysfunction
• septic organ failure and multiorgan failure e.g., acute respiratory distress syndrome (ARDS), acute lung injury (ALI), septic shock, DIC (disseminated intravascular coagulation or consumption coagulopathy) and/or septic organ failure.
• ARDS acute respiratory distress syndrome
• ALI acute lung injury
• DIC disseptic shock
• DIC disseptic intravascular coagulation or consumption coagulopathy
• SIRS systemic inflammatory response syndrome
• ACCP/SCCM Consensus Conference Committee from 1992 (Crit. Care Med 1992; 20:864-874) describes the diagnosis symptoms and measuring parameters required for the diagnosis “SIRS” (inter alia body temperature change, increased pulse, breathing difficulties and changed blood picture).
• SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference essentially kept the criteria, but fine-tuned details (Levy et al., Crit. Care Med 2003; 31:1250-1256).
• DIC coagulated intravascular coagulation or consumption coagulopathy
• endothelial damage with increased permeability of the vessels and seeping of fluids and proteins into the extravasal lumen.
• an organ for example kidney failure, liver failure, respiratory failure, central-nervous deficits and/or cardiovascular failure
• Septic shock refers to the onset of hypotension requiring treatment, which hypotension promotes further organ damage and is associated with a worsening of the prognosis.
• Pathogens may be bacteria (Gram-negative and Gram-positive), fungi, viruses and/or eukaryotes. Entrance point or primary infection may be, for example, pneumonia, an infection of the urinary tract or peritonitis. Infection can be, but is not necessarily, associated with bacteraemia.
• DIC and/or SIRS may occur during sepsis, but also as a result of operations, tumour diseases, burns or other injuries.
• DIC there is a massive activation of the coagulatory system at the surface of damaged endothelial cells, the surfaces of foreign bodies or injured extravascular tissue.
• coagulation factors for example factor X, prothrombin and fibrinogen
• platelets which reduces the ability of the blood to coagulate and may result in serious bleeding.
• the invention furthermore provides medicaments comprising a compound according to the invention and one or more further active compounds, in particular for the treatment and/or prophylaxis of the disorders mentioned above.
• exemplary and preferred active compounds for combinations are:
• antibiotics or antifungal medicament combinations are suitable, either as calculated therapy (prior to the presence of the microbrial diagnosis) or as specific therapy.
• norepinephrins for example norepinephrins, dopamines or vasopressin
• hydrocortisone for example hydrocortisone, or fludrocortisone
• erythrocyte concentrates for example erythrocyte concentrates, platelet concentrates, erythropietin or fresh frozen plasma
• Sedation for example diazepam, lorazepam, midazolam or propofol.
• Opioids for example fentanyl, hydromorphone, morphine, meperidine or remifentanil.
• NSAIDs for example ketorolac, ibuprofen or acetaminophen.
• Neuromuscular blockade for example pancuronium
• insulin for example insulin, glucose
• heparins for example for thrombosis prophylaxis or renal replacement methods, for example unfractionated heparins, low-molecular-weight heparins, heparinoids, hirudin, bivalirudin or argatroban.
• H2-receptor inhibitors for example H2-receptor inhibitors, antacids.
• the compounds according to the invention can also be used for preventing coagulation ex vivo, for example for preserving blood and plasma products, for cleaning/pretreatment of catheters and other medicinal aids and instruments, for coating synthetic surfaces of medicinal aids and instruments used in vivo or ex vivo or for biological samples comprising factor Xa.
• the present invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
• the present invention furthermore provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
• the present invention furthermore provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an anticoagulatory effective amount of the compound according to the invention.
• the present invention furthermore provides a method for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples containing factor Xa, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.
• the present invention furthermore provides combinations of
• compounds of the formula (I) with other pharmaceutically active compounds, in particular with platelet aggregation inhibitors, anticoagulants, fibrinolytics, lipid-lowering substances, coronary therapeutics and/or vasodilators.
• “Combinations” in the sense of the invention are to be understood as including not only administration forms comprising all components (so-called fixed combinations) and combination packages comprising the components separated from one another, but also components administered simultaneously or at different points in time, when they are used for the prophylaxis and/or treatment of the same disease. It is also possible to combine two or more active compounds with one another, these thus being two- or multi-component combinations.
• Platelet aggregation inhibitors are, for example, acetylsalicylic acid (such as, for example, aspirin), ticlopidin (ticlid), clopidogrel (plavix) and prasugrel,
• glycoprotein-IIb/IIIa antagonists such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban.
• Anticoagulatory effective substances are, for example, heparin (UFH), low-molecular-weight heparins (NMH), such as, for example, tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid,
• ORG42675 (Organon International Inc., Company World Wide Website 2007, April),
• DTI direct thrombin inhibitors
• Direct thrombin inhibitors are, for example:
• Plasminogen activators are, for example, tissue plasminogen activator (t-PA), streptokinase, reteplase and urokinase.
• Lipid-lowering substances are in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, such as, for example, lovastatin (mevacor; U.S. Pat. No. 4,231,938), simvastatin (zocor; U.S. Pat. No. 4,444,784), pravastatin (pravachol; U.S. Pat. No. 4,346,227), fluvastatin (lescol; U.S. Pat. No. 5,354,772) and atorvastatin (lipitor; U.S. Pat. No. 5,273,995).
• HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
• lovastatin mevacor; U.S. Pat. No. 4,231,938
• simvastatin zocor; U.S. Pat. No. 4,444,784
• pravastatin pravachol
• fluvastatin
• Coronary therapeutic/vasodilators are in particular ACE (angiotensin converting enzyme) inhibitors, such as, for example, captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin II) receptor antagonists, such as, for example, embusartan (U.S. Pat. No.
• ACE angiotensin converting enzyme
• losartan valsartan, irbesartan, candesartan, eprosartan and temisartan, or ⁇ -adrenoceptor antagonists, such as, for example, carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propanolol and timolol, or alpha-1-adrenoceptor antagonists, such as, for example, prazosine, bunazosine, doxazosine and terazosine, or diuretics, such as, for example, hydrochlorothiazide, furosemide, bumetanide, piretanide, torasemide, amiloride and dihydralazine, or calcium channel blockers, such as, for example, hydrochloro
• the present invention further relates to medicaments which comprise at least one compound according to the invention, normally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.
• the present invention furthermore provides medicaments comprising a compound according to the invention and one or more other of the active compounds for combination mentioned above, in particular for the treatment and/or prophylaxis of the disorders mentioned above.
• the compounds according to the invention can act systemically and/or locally.
• they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route or as implant or stent.
• the compounds according to the invention can be administered in administration forms suitable for these administration routes.
• Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds according to the invention rapidly and/or in modified fashion, and which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• tablets uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention
• tablets which disintegrate rapidly in the mouth or films/wafers, films/lyophilisates
• capsules for example hard or soft gelatin capsules
• Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
• Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents.
• pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
• nasal drops solutions or sprays
• tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems
• Oral or parenteral administration is preferred, especially oral administration.
• the compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colours (e.g. inorganic pigments such as, for example, iron oxides) and masking flavours and/or odours.
• carriers for example microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• parenteral administration amounts of about 0.001 to 5 mg/kg, preferably about 0.01 to 1 mg/kg, of body weight to achieve effective results, and on oral administration the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and very particularly preferably 0.1 to 10 mg/kg, of body weight.
• Method 1 Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of perchloric acid (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 6.5 min 90% B ⁇ 6.7 min 2% B ⁇ 7.5 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
• Method 2 Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of perchloric acid (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 9 min 0% B ⁇ 9.2 min 2% B ⁇ 10 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
• Method 3 MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm ⁇ 4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.
• Method 4 MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3 ⁇ 30 mm ⁇ 3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.
• Method 5 Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; column: Phenomenex Gemini 3 ⁇ 30 mm ⁇ 3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 208-400 nm.
• Method 6 Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; column: Thermo HyPURITY Aquastar 3 ⁇ 50 mm ⁇ 2.1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 5.5 min 10% A; oven: 50° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
• Method 7 Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of perchloric acid (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 15 min 90% B ⁇ 15.2 min 2% B ⁇ 16 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
• Method 8 MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance 2795; column: Phenomenex Onyx Monolithic C18, 100 mm ⁇ 3 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A; flow rate: 2 ml/min; oven: 40° C.; UV detection: 210 nm.
• Method 9 Instrument: Micromass GCT, GC6890; column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant helium flow: 0.88 ml/min; oven: 60° C.; inlet: 250° C.; gradient: 60° C. (maintained for 0.30 min), 50° C./min ⁇ 120° C., 16° C./min ⁇ 250° C., 30° C./min ⁇ 300° C. (maintained for 1.7 min).
• Method 10 Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min ⁇ 310° C. (maintained for 3 min).
• Method 11 Column: GROM-SIL 1200DS-4 HE, 10 ⁇ M, 250 mm ⁇ 30 mm; flow rate: 50 ml/min; mobile phase and gradient program: acetonitrile/0.1% aqueous formic acid 10:90 (0-3 min), acetonitrile/0.1% aqueous formic acid 10:90 ⁇ 95:5 (3-27 min), acetonitrile/0.1% aqueous formic acid 95:5 (27-34 min), acetonitrile/0.1% aqueous formic acid 10:90 (34-38 min); temperature: 22° C.; UV detection: 254 nm.
• the organic extract is washed successively with water and saturated sodium chloride solution.
• the extract is dried over anhydrous magnesium sulphate and then filtered, and the filtrate is freed from the solvent under reduced pressure.
• the residue is purified by filtration with suction through silica gel using cyclohexane/ethyl acetate 1:1 as mobile phase. This gives 1.38 g (98% of theory) of the title compound.
• this solution of the zinc enolate is, with the aid of a syringe, transferred into another flask containing a solution of 1.50 g (3.60 mmol) of, 103 mg (0.180 mmol) of bis(dibenzylideneacetone)palladium(0) and 106 mg (0.270 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 8 ml of anhydrous THF.
• the reaction mixture is heated at reflux for 19 hours.
• the THF is then removed on a rotary evaporator, and the residue is taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous sodium sulphate, filtration and concentration using a rotary evaporator, the product is purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 1:1 as mobile phase. This gives 1.12 g (78% of theory) of the title compound.
• reaction mixture is subsequently stirred at room temperature for 30 minutes. Moderate evolution of gas. 20 ml of water are then added, and the organic phase is separated off, dried over anhydrous sodium sulphate, filtered and concentrated using a rotary evaporator.
• the crude product is purified by filtration with suction through silica gel using cyclohexane/ethyl acetate 4:1 as mobile phase. This gives 1.75 g (84% of theory) of a liquid.
• the crude product is initially freed from coarse impurities by filtration with suction through silica gel using cyclohexane/ethyl acetate 5:1 ⁇ 1:1 as mobile phase.
• the product is then isolated by preparative HPLC. To this end, 2.1 g of the crude product obtained are dissolved in 5 ml of acetonitrile and chromatographed in 10 portions.
• the mixture of diastereomers from Example 5 is separated chromatographically into the pure diastereomers.
• 432 mg of the compound from Example 5 are dissolved in a mixture of 10 ml of methanol, 10 ml of tert-butyl methyl ether and 5 ml of acetonitrile and chromatographed in ten portions. This gives 182 mg (42% of theory) of the title compound (diastereomer 1) and 156 mg (36% of theory) of diastereomer 2.
• the mixture of diastereomers from Example 5 is separated chromatographically into the pure diastereomers.
• 432 mg of the compound from Example 5 are dissolved in a mixture of 10 ml of methanol, 10 ml of tert-butyl methyl ether and 5 ml of acetonitrile and chromatographed in ten portions. This gives 156 mg (36% of theory) of the title compound (diastereomer 2) and 182 mg (42% of theory) of diastereomer 1.
• Chromathographic method column: Kromasil 100C18, 5 ⁇ m, 250 mm ⁇ 20 mm; flow rate: 25 ml/min; temperature: 40° C.; UV detection: 210 nm; mobile phase: water/acetonitrile 3:1.
• the compounds according to the invention act in particular as inhibitors of blood coagulation factor Xa and do not, or only at significantly higher concentrations, inhibit other serine proteases, such as plasmin or trypsin.
• FXa human factor Xa
• Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations are carried out in microtitre plates as follows:
• the chromogenic substrate 150 ⁇ mol/l of Pefachrome® FXa from Pentapharm
• the extinction at 405 nm is determined. The extinctions of the test mixtures containing the test substance are compared with control mixtures without test substance, and the IC 50 values are calculated from these data.
• FXa human factor Xa
• Substances to be tested are dissolved in dimethyl sulphoxide and incubated for 15 min at 22° C. with human FXa (1.3 nmol/l dissolved in 50 mmol/l of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/l NaCl, 0.1% BSA [bovine serum albumin], pH 7.4).
• the fluorogenic substrate (5 ⁇ mol/l of Boc-Ile-Glu-Gly-Arg-AMC from Bachem) is then added. After an incubation time of 30 min, the sample is excited at a wavelength of 360 nm, and the emission at 460 nm is measured.
• the measured emissions of the test batches with test substance are compared to the control batches without test substance (only dimethyl sulphoxide instead of test substance in dimethyl sulphoxide), and IC 50 values are calculated from the concentration/activity relationships.
• test substances are examined for their inhibition of other human serine proteases, such as thrombin, trypsin and plasmin.
• other human serine proteases such as thrombin, trypsin and plasmin.
• trypsin 500 mU/ml
• plasmin 3.2 nmol/l
• the enzymatic reaction is then started by addition of the appropriate specific chromogenic substrates (Chromozym Thrombin®, Chromozym Trypsin® and Chromozym Plasmin®; from Roche Diagnostics), and after 20 minutes the extinction is determined at 405 nm. All determinations are carried out at 37° C. The extinctions of the test batches with test substance are compared to the control samples without test substance, and the IC 50 values are calculated from these data.
• the appropriate specific chromogenic substrates Chromozym Thrombin®, Chromozym Trypsin® and Chromozym Plasmin®; from Roche Diagnostics
• test substances are examined for their inhibition of other human serine proteases, such as thrombin, trypsin and plasmin.
• thrombin a human serine proteases
• trypsin 83 mU/ml from Sigma
• plasmin 0.1 ⁇ g/ml from Kordia
• these enzymes are dissolved (50 mmol/l of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/l of NaCl, 0.1% BSA [bovine serum albumin], 5 mmol/l of calcium chloride, pH 7.4) and incubated for 15 min with various concentrations of test substance in dimethyl sulphoxide and also with dimethyl sulphoxide without test substance.
• the enzymatic reaction is then started by addition of the appropriate substrates (5 ⁇ mol/l of Boc-Asp(OBzl)-Pro-Arg-AMC from Bachem for thrombin, 5 ⁇ mol/l of Boc-Ile-Glu-Gly-Arg-AMC from Bachem for trypsin and 50 ⁇ mol/l of MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin).
• the fluorescence is measured (excitation: 360 nm, emission: 460 nm).
• the measured emissions of the test batches with test substance are compared to the control batches without test substance (only dimethyl sulphoxide instead of test substance in dimethyl sulphoxide), and IC 50 values are calculated from the concentration/activity relationships.
• the anticoagulatory activity of the test substances is determined in vitro in human and rabbit plasma.
• blood is drawn off in a mixing ratio of sodium citrate/blood of 1:9 using a 0.11 molar sodium citrate solution as receiver.
• the blood is mixed thoroughly and centrifuged at about 2500 g for 10 minutes.
• the supernatant is pipetted off.
• the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Hemoliance® RecombiPlastin, from Instrumentation Laboratory).
• the test compounds are incubated with the plasma at 37° C. for 3 minutes. Coagulation is then started by addition of thromboplastin, and the time when coagulation occurs is determined.
• the concentration of test substance which effects a doubling of the prothrombin time is determined.
• the activity of thrombin in coagulating plasma is determined by measuring the fluorescent cleavage products of the substrate I-1140 (Z-Gly-Gly-Arg-AMC, Bachem).
• the reactions are carried out in 20 mM Hepes, 60 mg/ml of BSA, 102 mM CaCl 2 , pH 7.5 at 37° C.
• the reactions are carried out in Immulon 2HB clear U-bottom 96-well plates (Thermo Electron) in a total volume of 100 ⁇ l.
• PPP platelet-poor plasma
• PRP platelet-rich plasma
• reagents from Thrombinoscope are used (PPP reagent: 30 pM recombinant tissue factor, 24 ⁇ M phospholipids in HEPES; PRP reagent: 3 pM recombinant tissue factor).
• PPP reagent 30 pM recombinant tissue factor, 24 ⁇ M phospholipids in HEPES
• PRP reagent 3 pM recombinant tissue factor
• a calibrator whose amidolytic activity is needed for calculating the thrombin activity in a sample containing an unknown amount of thrombin.
• the calibrator also allows the data to be corrected for donor variability (different coloration of the plasma), variability by the measuring instrument, the inner filter effect and the substrate consumption.
• the measurement is carried out using a fluorometer (Fluoroskan Ascent) from Thermo Electron fitted with a 390/460 nM filter pair and a dispenser. Practice of the test: the lyophilisates are dissolved (PPP reagent, PRP reagent, calibrator), the MTPs are incubated at 37° C.
• FluCa is prepared (70 ⁇ l of I-1140+2800 ⁇ l of Fluo buffer (20 mM HEPES, 102 mM CaCl 2 , 60 mg/ml of BSA, pH 7.5) per plate), the program is started, the dispenser is flushed and the system is filled with FluoCa, 20 ⁇ l of FluoCa per well are added and thrombin generation is measured every 20 s, (or in the case of animal plasma every 10 s) over 120 min. The thrombogram is calculated and represented graphically using the thrombinoscope software.
• lag time time until the generation of thrombin starts
• ttPeak time to peak, time until the maximum is reached
• peak maximum thrombin concentration
• ETP endogenous thrombin potential, the area under the curve
• start tail the point in time when the thrombin concentration goes back to 0
• TAT Thrombin/antithrombin complexes
• Plasma is obtained from citrated blood by centrifugation. 50 ⁇ l of TAT sample buffer are added to 50 ⁇ l of plasma, and the sample is shaken briefly and incubated at room temperature for 15 min. The samples are filtered off with suction, and the well is washed 3 times with wash buffer (300 ⁇ l/well). Between the washing stages, the liquid is removed by tapping the plate.
• Conjugate solution (100 ⁇ l) is added, and the plate is incubated at room temperature for 15 min. The samples are sucked off, and the well is washed 3 times with wash buffer (300 ⁇ l/well). Chromogenic substrate (100 ⁇ l/well) is then added, the plate is incubated in the dark at room temperature for 30 min, stop solution is added (100 ⁇ l/well) and the colour development is measured at 492 nm (Saphire plate reader).
• the extent of the inflammatory reaction triggered by endotoxin can be detected by the increase of inflammation mediators, for example interleukins (1, 6, 8 and 10), tumour necrosis factor alpha or monocyte chemoattractant protein-1 in the plasma.
• inflammation mediators for example interleukins (1, 6, 8 and 10
• tumour necrosis factor alpha for example monocyte chemoattractant protein-1
• monocyte chemoattractant protein-1 for example interleukins (1, 6, 8 and 10
• ELISAs or the luminex system may be used.
• Fasting rabbits (strain: Esd: NZW) are anaesthetized by intramuscular administration of Rompun/Ketavet solution (5 mg/kg and 40 mg/kg, respectively). Thrombus formation is initiated in arteriovenous shunt in accordance with the method described by C. N. Berry et al. [ Semin. Thromb. Hemost. 1996, 22, 233-241]. To this end, the left jugular vein and the right carotid artery are exposed. The two vessels are connected by an extracorporeal shunt using a vein catheter of a length of 10 cm.
• this catheter is attached to a further polyethylene tube (PE 160, Becton Dickenson) of a length of 4 cm which contains a roughened nylon thread which has been arranged to form a loop, to form a thrombogenic surface.
• PE 160 polyethylene tube
• the extracorporeal circulation is maintained for 15 minutes.
• the shunt is then removed and the nylon thread with the thrombus is weighed immediately.
• the weight of the nylon thread on its own was determined before the experiment was started.
• the test substances are administered either intravenously via an ear vein or orally using a pharyngeal tube.
• Fasting rats are anaesthetized by intraperitoneal administration of thiobarbital-sodium (180 mg/kg).
• Arterial thrombus formation is triggered at the carotid artery similarly to the method described by Kurz et al. [Thromb Res. 1990 Nov. 15; 60(4):269-80].
• the right carotid artery is exposed, and a flow sensor is fixed at the vessel (perivascular probe).
• a filter paper is drenched with 25% strength iron(III) chloride solution and pushed under the carotid artery; in some protocol versions, the filter paper is removed again after a defined period of time (for example after 5 minutes).
• test substances are administered either intravenously via an ear vein or orally using a pharyngeal tube.
• the following parameters are stated: the point in time when the flow starts to be reduced (start of thrombus formation); speed of flow reduction (speed of thrombus formation); occurrence of complete occlusion and interval until complete occlusion.
• Venous thrombae are generated using a combination of circulatory arrest and thromboplastin injection.
• Male rats (HSD CPB:WU; Harlan Winkelmann) having a weight of 220 g-260 g are fasted overnight. Water is available ad libitum.
• the animals Prior to the start of the test, the animals are anaesthetized by intraperitoneal administration of a xylazine/ketamine mixture (5 ml/kg) (Rompun Bayer 12 mg/kg, Ketavet Pharmacia & Upjohn GmbH, 50 mg/kg).
• thromboplastin (Neoplastin Plus, Diagnostica Stago, Roche) is injected over a period of 15 seconds into the jugular vein (0.5 mg/kg in 1 ml/kg). After a further 15 seconds, the vena cava is tied off, initially proximally and then, after 30 seconds, distally. The ligated segment of the vein is excised 15 minutes after the thromboplastin injection. The thrombus is exposed and weighed immediately. The inhibitors to be examined (1 ml/kg) are administered intravenously to the animals prior to the preparation.
• Fasting male rats (strain: HSD CPB:WU) having a weight of 300-350 g are anaesthetized using Inactin (150-180 mg/kg).
• Inactin 150-180 mg/kg.
• the tip of the tail of the rats is docked by 3 mm using a razor blade.
• the tail is then placed into physiological saline solution kept at a temperature of 37° C., and the bleeding from the cut is observed over a period of 15 min. What is determined are the time until bleeding ceases for at least 30 seconds (initial bleeding time), total bleeding time over a period of 15 minutes (cumulative bleeding time) and the quantitative blood loss via photometric determination of the collected haemoglobin.
• test substances are administered to the animals while awake either intravenously via the contralateral jugular vein as a single bole or as a bole with subsequent continuous infusion or orally using a pharyngeal tube.
• Fasting rats are anaesthetized by intraperitoneal administration of thiobarbital-sodium (Inactin) (180 mg/kg).
• a catheter PE 190
• a catheter PE 190
• the substances are administered orally at various points in time prior to blood withdrawal.
• the substances are administered in dosages of 1 and 5 mg/kg p.o. and blood is in each case withdrawn at a later point in time (6 and 10 hours after substance administration).
• Calibration solution 1 (20 ⁇ g/ml): 1000 ⁇ l of DMSO are added to 34.4 ⁇ l of the stock solution, and the mixture is homogenized.
• Calibration solution 2 (2.5 ⁇ g/ml): 700 ⁇ l of DMSO are added to 100 ⁇ l of calibration solution 1, and the mixture is homogenized.
• Sample solution for solubilities of up to 10 g/l in PBS buffer pH 7.4 About 5 mg of the active compound are weighed accurately into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120.094), and PBS buffer pH 7.4 is added to a concentration of 5 g/l (for example 5 mg of active compound+500 ⁇ l of PBS buffer pH 7.4).
• Sample solution for solubilities of up to 10 g/l in acetate buffer pH 4.6 About 5 mg of the active compound are weighed accurately into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120.094), and acetate buffer pH 4.6 is added to a concentration of 5 g/l (for example 5 mg of active compound+500 ⁇ l of acetate buffer pH 4.6).
• Sample solution for solubilities of up to 10 g/l in water About 5 mg of the active compound are weighed accurately into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120.094), and water is added to a concentration of 5 g/l (for example 5 mg of active compound+500 ⁇ l of water).
• sample solutions prepared in this manner are shaken at 1400 rpm in a temperature-adjustable shaker (for example Eppendorf Thermomixer comfort Art. No. 5355 000.011 with interchangeable block Art. No. 5362.000.019) at 20° C. for 24 hours. In each case 180 ⁇ l are taken from these solutions and transferred into Beckman Polyallomer centrifuge tubes (Art. No. 343621). These solutions are centrifuged at about 223 000 *g for 1 hour (for example Beckman Optima L-90K ultracentrifuge with type 42.2 Ti rotor at 42 000 rpm).
• the samples are analyzed by RP-HPLC. Quantification is carried out using a two-point calibration curve of the test compound in DMSO. The solubility is expressed in mg/l.
• Calibration solution 2.5 mg/ml Calibration solution 20 ⁇ g/ml Sample solution 1:5 Sample solution 1:100 Sample solution 1:1000
• Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: Phenomenex Gemini C18, 50 ⁇ 2 mm, 5 ⁇ ; temperature: 40° C.; mobile phase A: water/phosphoric acid pH 2; mobile phase B: acetonitrile; flow rate: 0.7 ml/min; gradient: 0-0.5 min 85% A, 15% B; ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; ramp: 3.5-4 min 85% A, 15% B; 4-5 min 85% A, 15% B.
• Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: VDSoptilab Kromasil 100C18, 60 ⁇ 2.1 mm, 3.5 p; temperature: 30° C.; mobile phase A: water+5 ml perchloric acid/l; mobile phase B: acetonitrile; flow rate: 0.75 ml/min; gradient: 0-0.5 min 98% A, 2% B; ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
• test substances are dissolved in various formulating compositions (for example plasma, ethanol, DMSO, PEG400, etc.) or mixtures of these solubilizers and administered intravenously or perorally in male or female Wistar rats.
• Intravenous administration is carried out either as a bolus injection or as an infusion.
• the doses administered are in the range from 0.1 to 5 mg/kg.
• Blood samples are taken by means of a catheter or as sacrifice plasma at various times over a period of up to 26 h. Quantitative determination of the substances in the test samples takes place in plasma using calibration samples adjusted in plasma. Proteins present in the plasma are removed by precipitation with acetonitrile.
• the samples are then fractionated by HPLC using reversed-phase columns in a 2300 HTLC system (Cohesive Technologies, Franklin, Mass., USA).
• the HPLC system is coupled via a turbo ion spray interface to an API 3000 Triple Quadropole mass spectrometer (Applied Biosystems, Darmstadt, Germany).
• the plasma concentration time course is analyzed using a validated kinetic analysis program.
• the examination is carried out using rats or mice.
• LPS Escherichia coli serotype 055:B5, Sigma-Aldrich
• the test substances are administered up to one hour prior to the LPS injection either intravenously via the tail vein, subcutaneously, intraperitoneally or orally using a pharyngeal tube.
• the animal is anaesthetized (Ketavet/Rompun) and the abdomen is opened by surgery.
• Sodium citrate solution (3.2% w/v) (formula: body weight in g/13 times 100 ⁇ l) is injected into the lower vena carva, and a blood sample (about 1 ml) is taken after 30 sec.
• Various parameters for example cellular blood components (in particular erythrocytes, leukocytes and platelets), lactate concentration, coagulation activation (TAT) or parameters of organ dysfunction or organ failure and mortality are determined from the blood.
• LPS E. coli 055 B5, manufactured by Sigma, dissolved in PBS
• the test substance is dissolved in PEG 400/H 2 O 60%/40% and administered orally (administration volume 5 ml/kg) 30 minutes prior to the LPS injection.
• the animals are exsanguinated by puncture of the heart in terminal anaesthesia (Trapanal® 100 mg/kg i.p.), and citrate plasma is obtained for the determination of fibrinogen, PT, TAT and platelet number.
• serum is obtained for the determination of liver enzymes, kidney function parameters and cytokines. TNF ⁇ and IL-6 are determined using commercially available ELISAs (R&D Systems).
• the compounds according to the invention can be converted into pharmaceutical preparations in the following ways:
• the mixture of the compound according to the invention, lactose and starch is granulated with a 5% strength solution (m/m) of PVP in water.
• the granules are dried and then mixed with the magnesium stearate for 5 minutes.
• This mixture is compressed using a conventional tablet press (see above for format of the tablet).
• a compressive force of 15 kN is used for the compression.
• 10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound according to the invention.
• Rhodigel is suspended in ethanol, and the compound according to the invention is added to the suspension.
• the water is added while stirring.
• the mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.
• the compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate while stirring. Stirring is continued until the compound according to the invention is completely dissolved.
• the compound according to the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (for example isotonic sodium chloride solution, glucose solution 5% and/or PEG 400 solution 30%).
• a physiologically acceptable solvent for example isotonic sodium chloride solution, glucose solution 5% and/or PEG 400 solution 30%.
• the solution is sterilized by filtration and filled into sterile and pyrogen-free injection containers.

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